Arginine vasopressin (AVP) is an antidiuretic hormone of a peptide comprising 9 amino acids as biosynthesized and secreted in a hypothalamohypophysial system and is known to have an action to promote water reabsorption in a kidney distal uriniferous tubule, contract a blood vessel and elevate a blood pressure and to act as a neurotransmitter, etc. in a brain.
As a receptor of AVP, there are known three kinds of subtypes of V1A, V1B and V2. An AVP receptor antagonist to competitively inhibit the binding to the V1A and/or V2 receptor of AVP is expected as a drug for suppressing contraction of a vascular smooth muscle and suppressing pressure rise or as a drug for suppressing water reabsorption in a kidney collecting tubule, or as a drug having a combination of these actions (see NIPPONRINSHO, Vol. 58, Special Issue, “Hypertension (the Last Volume)”, pp. 292–296 (2000)).
On the other hand, with the diversification of medical treatment and the age advance, it has become uncommon to use a drug singly, and in the most case, a plurality of drugs are administered simultaneously or while shifting the administration time. This is also applicable in the field of the AVP receptor antagonist. The drug is inactivated in a liver due to the action of drug metabolizing enzymes and converted into a metabolite. Among these drug metabolizing enzymes, cytochrome P450 (CYP) is the most important. CYP includes many molecular species. When a plurality of drugs metabolized from CYP of the same molecular species compete on the metabolizing enzyme thereof, it is considered that the drug receives some metabolic inhibition depending on the affinity of the drug with CYP. As a result, drug interactions such as rise of concentration in blood and prolongation of half-life in blood are revealed.
Such drug interactions are not preferred except the case where the drug is used with the intention of revealing an additive action or potentiation, and there may be the case where an unexpected side effect is revealed. Accordingly it is demanded to create a drug having a low affinity with CYP and a little possibility of the drug interaction.
Hitherto, as the foregoing AVP receptor antagonist, compounds of a peptide type and compounds of a non-peptide type have been synthesized (see, for example, JP-A-2-32098, WO 91/05549, EP0382185, WO 93/03013, WO 95/03305, WO 95/06035, and WO 97/15556).
Among them, WO 95/03305 discloses that a condensed benzazepine derivative represented by the following general formula or its salt is useful as an AVP receptor antagonist.
(In the formula, the symbols are as defined in the patent document.)
That is, this patent document describes some condensed benzazepine derivatives and salts thereof but does not disclose at all the compounds of the invention, wherein the ring B represents an optionally substituted nitrogen-containing aromatic 5-membered ring having at least one nitrogen atom and further optionally having one oxygen or sulfur atom; R1 represents a hydrogen atom; A represents —NHCO—(CR3R4)n—; n is 0; and the ring C represents an optionally substituted benzene ring. Further, this patent document describes the V1 and/or V2 receptor antagonism of AVP but does not mention the inhibition activity against the drug metabolizing enzyme CYP.
As described previously, as the AVP receptor antagonist, the compounds as described in the above-cited patent documents are known. But, it is an important problem from the standpoint of medical treatment to create a more superior AVP receptor antagonist and to create an AVP receptor antagonist free from side effects based on the inhibition of the drug metabolizing enzyme CYP.